Myoblast differentiation, adipocyte differentiation and NF-kB activation are considered to play an important role in various diseases. For example, in diseases such as diabetes, obesity, dyslipidemia and the like, it is considered that suppression of myoblast differentiation, promotion of adipocyte differentiation, or promotion of NF-kB activation is involved in the onset and aggravation of the diseases. In fact, obesity wherein adipose tissue amount has increased is a risk factor of diabetes, hypertension, dyslipidemia and the like, and it has been reported that muscle mass decreases in diabetes and obesity. Diabetes (2006)55, 1813-1818 (non-patent document 1) describes that type 2 diabetes patients show decreased muscle mass, and Mechanisms of Ageing and Development (2003)124, 495-502 (non-patent document 2) teaches that obesity of body trunk and decrease of muscle mass are related. It has also been reported that the muscle mass increases when NF-kB pathway is suppressed by a proteasome inhibitor.
Skeletal muscles, which are present in human in not less than 600, are tissues occupying the largest proportion of the body weight, and consume sugar by insulin stimulation. On the other hand, obesity is a condition showing an increased amount of adipose tissue, and it is considered that metabolic disorder or organ damage occur due to insulin resistance caused by decreased adiponectin secretion and promoted secretion of inflammatory cytokines such as TNF-α and the like from obese adipocyte, and the like, and the like. Therefrom, increase of muscle mass and suppression of adipocyte differentiation are considered to be useful for the improvement of glycolipid metabolism.
Steroid hormone is known to increase the muscle mass. However, steroid hormone is also known to cause various side effects. While use of a myostatin antibody and a soluble receptor of activin, which is a myostatin receptor, to increase the muscle mass is being studied, it has not been put to practical use. In addition, an adipocyte differentiation suppressive action of a steroid hormone, a myostatin antibody or a soluble receptor of activin has not been reported.
There is still a high need for an agent for the prophylaxis or treatment of diabetes, obesity, dyslipidemia and the like, and the development of a strong therapeutic drug with fewer side effects is desired.
U.S. 2005/0277638 (patent document 1) and U.S. 2005/0137243 (patent document 2) disclose that a compound represented by the following formula
wherein A is selected from the group consisting of —C(O)—, —S(O)—, —S(O)2—, —C(═NRa)— and —C(═S)—;    B is selected from the group consisting of alkylene, alkenyl, carbonylalkyl, cycloalkyl, —NRb— and —NRb-alkyl;    D is a bond or selected from the group consisting of alkylene, aryl, arylalkyl, heterocyclyl and heterocyclylalkyl;    E is selected from the group consisting of alkyl, alkyl-C(O)—, alkyl-C(O)—NH—, alkyl-NH—, alkyl-NH—C(O)—, alkyl-NH—S(O)2—, alkoxy, alkyl-S—, alkyl-S(O)2—, alkyl-S(O)2—NH—, aryl, aryl-C(O)—, aryl-C(O)—NH—, aryl-C═N—O—, aryl-NH—, aryl-NH—C(O)—, aryl-NH—S(O)2—, aryloxy, aryl-S—, aryl-S-alkyl-C(O)—, aryl-S(O)2—, aryl-S(O)2—NH—, arylalkyl-C(O)—, arylalkyl-C(O)—NH—, arylalkyl-NH—, arylalkyl-NH—C(O)—, arylalkyl-NH—S(O)2—, arylalkoxy, arylalkyl-S—, arylalkyl-S(O)2—, arylalkyl-S(O)2—NH—, cycloalkyl, cycloalkyl-C(O)—, cycloalkyl-C(O)—NH—, cycloalkyl-NH—, cycloalkyl-NH—C(O)—, cycloalkyl-NH—S(O)2—, cycloalkoxy, cycloalkyl-S—, cycloalkyl-S(O)2—, cycloalkyl-S(O)2—NH—, cycloalkenyl, cycloalkenylalkyl, cycloalkenyl-C(O)—, cycloalkenyl-C(O)—NH—, cycloalkenyl-NH—, cycloalkenyl-NH—C(O)—, cycloalkenyl-NH—S(O)2—, cycloalkenyloxy, cycloalkenyl-S—, cycloalkenyl-S(O)2—, cycloalkenyl-S(O)2—NH—, heterocyclyl, heterocyclyl-C(O)—, heterocyclyl-C(O)—NH—, heterocyclyl-NH—, heterocyclyl-NH—C(O)—, heterocyclyl-NH—S(O)2—, heterocyclyl-O—, heterocyclyl-S—, heterocyclyl-S(O)2—, heterocyclyl-S(O)2—NH—, heterocyclylalkyl-C(O)—, heterocyclylalkyl-C(O)—NH—, heterocyclylalkyl-NH—, heterocyclylalkyl-NH—C(O)—, heterocyclylalkyl-NH—S(O)2—, heterocyclylalkyl-O—, heterocyclylalkyl-S—, heterocyclylalkyl-S(O)2— and heterocyclylalkyl-S(O)2—NH—;    R1 is selected from the group consisting of hydrogen and alkyl;    R2 is selected from the group consisting of hydrogen, halogen, alkyl and alkoxy;    R3 is RcRdR—;    R4 is selected from the group consisting of hydrogen and alkyl;    R4 and Rc are optionally bonded to each other to form a heterocycle;    R5 are each independently selected from the group consisting of hydrogen and alkyl;    Ra is selected from the group consisting of hydrogen and alkyl;    Rb is selected from the group consisting of hydrogen and alkyl;    Rb and R1 are optionally bonded to each other to form a heterocycle;    Rc and Rd are each selected from the group consisting of hydrogen atom, alkyl, aryl, arylalkyl, cycloalkyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl and hydroxyalkyl, or Rc and Rd are optionally bonded to each other to form a heterocycle;    Z is selected from the group consisting of hydrogen, alkyl and halogen;    m is 1, 2 or 3, provided when B is —NRb— or —NRb-alkyl, then D is selected from the group consisting of alkylene, aryl, arylalkyl, heterocyclyl and heterocyclylalkyl,and the like have prophylactic or treatment use for eating disorder, obesity, reproductive abnormality, mental diseases and the like, as melanin concentrating hormone antagonists.
In addition, WO 02/50091 (patent document 3) discloses that a compound represented by the following formula
wherein R is hydrogen, cyano, (CH2)nA-X—R4 or (CH2)nR5;    A is —N(R6)—, —N[C(O)R6]—, —N(R6)C(O)—, —N(R6)S(O)2—, —N(R6)C(O)O—, —N═C(R6)— or —N(R6)C(Y)N(R7)—;    R1 is C1-6 alkyl or C3-6 alkenyl;    R2 is hydrogen or a hydroxyl-protecting group;    R3 is hydrogen or halogen;    X is a bond, a C1-10 alkylene chain, a C2-10 alkenylene chain or a C2-10 alkynylene chain, wherein these chains are (i) optionally interrupted by a divalent group selected from —O—, —N(R8)—, —C(O)—, —N(R8)C(Y)N(R9)—, —S(O)m-, —N(R8)C(O)—, —C(O)N(R8)—, —N(R8)C(O)C(O)—, —C(O)O— and —C(NOR6)—, and/or (ii) optionally substituted by C1-4 alkyl, oxo, C1-4 alkoxy, halogen, cyano, phenoxy, hydroxy, NR8R9, N(R8)C(O)R9, ═NOR6, NR8C(Y)NR9 or optionally substituted phenyl;    R4 is hydrogen,    optionally substituted phenyl,    optionally substituted C3-7 cycloalkyl,    optionally substituted 9- or 10-membered fused bicyclic carbocyclyl,    optionally substituted 5- or 6-membered heteroaryl wherein the 5-membered heteroaryl contains at least one hetero atom from oxygen atom, sulfur atom and nitrogen atom, and the 6-membered heteroaryl contains 1 to 3 nitrogen atoms,    optionally substituted 5- or 6-membered heterocyclyl, or    R4 is optionally substituted 9- or 10-membered fused bicyclic heterocyclyl containing at least one hetero atom from oxygen atom, sulfur atom and nitrogen atom;    R5 is 5- or 6-membered heterocyclyl containing at least one nitrogen atom, which is optionally substituted by 1 or 2 substituents selected from oxo group and 9- or 10-membered fused bicyclic heterocyclyl containing at least one hetero atom selected from or oxygen atom, sulfur atom and nitrogen atom;    R6 and R7 are each independently a hydrogen atom, C1-4 alkyl, or phenyl optionally substituted by 1 or 2 C1-4 alkyl;    R8 and R9 are each independently hydrogen, phenyl (optionally substituted by 1 or 2 C1-4 alkyl), or R8 and R9 are each independently C1-4 alkyl optionally substituted by 1 or 2 substituents selected from phenyl, C1-4 alkoxy, cyano, 5-membered heteroaryl containing 1 or 2 hetero atoms selected from oxygen atom, sulfur atom and nitrogen atom, 6-membered heteroaryl containing 1 to 3 nitrogen atoms, hydroxy, oxo and carboxy;    Y is an oxygen atom or a sulfur atom;    n is an integer of 0 or 1 to 3; and    m is 0, 1 or 2,    and the like is applicable to prophylactic or therapeutic use for systemic or topical bacterial infection and the like.